The principle objective of this Project is to establish whether psychosocial, socio-environmental and lifestyle-related risk factors for cardiovascular disease are associated, individually and in aggregate, with interindividual variability in central nervous system serotonergic (5-HT) responsivity. Behavioral risk factors of interest include hostility, depression, low socio-economic status, social isolation (low social support), contemporaneous stress, smoking, imprudent diet, physical inactivity, and excessive consumption of alcohol. A second aim is to determine whether individual differences in central serotonergic responsivity also covary with preclinical indicators of vascular disease and cumulative risk factor exposure (viz., endothelium-mediated dilation of the branchial artery, carotid artery intimal-medial thickness and atherosclerotic plaque). A third aim is to determine whether population variability in central serotonergic function may be predicted, in part, by polymorphic variation in candidate genes of the 5-HT system. We propose to recruit a community sample of 600 men and women, 30-50 years of age and without clinical history of atherosclerotic cardiovascular disease. Subjects will be administered a neuropsychopharmacologic challenge to evaluate central serotonergic responsivity (plasma prolactin and ACTH responses to the 5-HT re-uptake inhibitor, citalopram) and data will be collected in each of the foregoing domains of behavioral risk for cardiovascular disease. The latter will include a batter of diagnostic and assessment interviews, as well as standardized questionnaires. Ultrasound evaluations of vascular reactivity and carotid artery disease will be obtained on 300 subjects, derived from the upper and lower tertiles on the distribution of central 5-HT responsivity (as indexed by subjects' citalopram-induced prolactin responses). In addition, blood for DNA analysis will be obtained from all study participants. Project 1 will provide a first systematic test of the hypothesis that diverse sources of behavior risk for cardiovascular disease aggregate, in part, under the influence of a common neurobiologic mechanism involving altered central serotonergic function. Support for this hypothesis will further our understanding of the origins of behavioral influences on heart disease and provide clues to possible commonalities of etiology and pathogenicity.